1. Alkyladenine DNA glycosylase associates with transcription elongation to coordinate DNA repair with gene expression
- Author
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Diana L. Bordin, Per Arne Aas, Marit Otterlei, Alessandro Brambilla, Nicolas Kunath, Magnar Bjørås, Antonia Furrer, Sarah L. Fordyce Martin, Stefano Bradamante, Pål Sætrom, Nicola P. Montaldo, Karine Øian Bjørås, Lene Christin Olsen, Barbara van Loon, Leona D. Samson, and Marcel Rösinger
- Subjects
0301 basic medicine ,Genome instability ,Transcription Elongation, Genetic ,DNA Repair ,DNA repair ,Science ,General Physics and Astronomy ,Gene Expression ,RNA polymerase II ,General Biochemistry, Genetics and Molecular Biology ,Article ,Genomic Instability ,DNA Glycosylases ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,RNA polymerase ,DNA-(Apurinic or Apyrimidinic Site) Lyase ,Humans ,lcsh:Science ,Gene ,Base excision repair ,Multidisciplinary ,biology ,General Chemistry ,DNA ,DNA Methylation ,Chromatin ,Cell biology ,030104 developmental biology ,HEK293 Cells ,chemistry ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,DNA methylation ,biology.protein ,lcsh:Q ,RNA Polymerase II ,Transcriptional Elongation Factors - Abstract
Base excision repair (BER) initiated by alkyladenine DNA glycosylase (AAG) is essential for removal of aberrantly methylated DNA bases. Genome instability and accumulation of aberrant bases accompany multiple diseases, including cancer and neurological disorders. While BER is well studied on naked DNA, it remains unclear how BER efficiently operates on chromatin. Here, we show that AAG binds to chromatin and forms complex with RNA polymerase (pol) II. This occurs through direct interaction with Elongator and results in transcriptional co-regulation. Importantly, at co-regulated genes, aberrantly methylated bases accumulate towards the 3′end in regions enriched for BER enzymes AAG and APE1, Elongator and active RNA pol II. Active transcription and functional Elongator are further crucial to ensure efficient BER, by promoting AAG and APE1 chromatin recruitment. Our findings provide insights into genome stability maintenance in actively transcribing chromatin and reveal roles of aberrantly methylated bases in regulation of gene expression., How genome stability is maintained at regions of active transcription is currently not entirely clear. Here, the authors reveal an association between base excision repair factors and transcription elongation to modulate DNA repair.
- Published
- 2019